17alpha-hydroxyaldosterones and processes for their manufacture



United States Patent 17a-HYDROXYALDOSTERONES AND PROCESSES FOR THEIRMANUFACTURE Derek H. R. Barton, Northwood, Middlesex, England, as-

signor to Schering Corporation, Bloomfield, N.J., a corporation of NewJersey N0 Drawing. Filed May 23, 1963, Ser. No. 282,562

14 Claims. (Ci. 260239.55)

This is a continuation-in-part of applications Serial No. 113,086, filedMay 29, 1961, and Serial No. 95,490, filed March 14, 1961, which, inturn, is a continuation-in-part of application Serial No. 19,444, filedApril 4, 1960, now abandoned.

This invention relates to novel cyclopentanophenanthrene derivatives, tomethods for their manufacture, and to novel intermediates producedthereby. More particularly, this invention relates to therapeuticallyactive 17ahydroxyaldosterones and derivatives thereof and to processesfor their manufacture, including novel intermediates useful therein.

Included among the compounds of my invention are l7a-hydroxyaldosteronederivatives of the following structural Formula I, the l-dehydro,G-dehydro, and 1,6-bisdehydro analogs thereof:

wherein A is a member selected from the group consisting of hydrogen andlower alkyl; B is a member selected from the group consisting ofhydrogen, methyl, and fluorine; X is a member selected from the groupconsisting of hydrogen and halogen; and R, R and R" are members selectedfrom the group consisting of hydrogen and lower alkanoyl.

Also included in my invention are [3,2-c]-pyrazole derivatives of thecompounds of Formula I and the 6- dehydro analogs thereof, particularly1- and 2'-substituted-[3,2-c]-pyrazoles. Preferred [3,2-c]-pyrazoles are2'-substituted derivatives of the following Formula II and the 6-dehydroanalogs thereof:

wherein A, B, X, and R, R and R are as defined in Formula I and Y is amember selected from the group consisting of phenyl and substitutedphenyl, e.g., p-fluorophenyl.

3,216,997 Patented Nov. 9, 1965 By lower alkyl is contemplatedhydrocarbon radicals having up to 4 carbon atoms, thus, includingmethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, andthe like.

The lower alkanoic acid-esters at C-17, 18, and 21 include hydrocarboncarboxylic acid radicals having up to 12 carbon atoms, such as acetate,propionate, valerate, t-butyl acetate, n-butyrate, enanthate, and thelike.

Included among the 17 a-hydroxyaldosterones of my invention arecompounds such as 17a-hydroxyaldosterone and the 9u-fluoroand9ix-bromo-derivatives thereof; 1711- hydroxy-1-dehydroaldosterone, the9a-fluoro-, 9114111010- 16a-methyl-, 9a-fluoro-16fl-methyl-, the6a-methyl-, 6afiuoro-, 6a,16a-dimethyl-, and 6a-fluoro-16t-methyl-derivatives thereof; and17a-hydroxy-1,6-bis-dehydroaldosterone, and the 9a-fluoroand9a-fluoro-16a-methyl-deriva tives thereof. Also included are[3,2-c1-pyrazole derivatives of l7a-hydroxyaldosterones, such as16z-methyl-1lfi, 18 oxido 4-pregnene-17a,18,21-triol-20-one-[3,2-c1-2'p-fiuorophenylpyrazole and the 9a-fiuoro-derivative thereof; 6,16ocdimethyl-l1,8,18-oxido=4,6-pregnadiene-17u,18, 21-triol-20-one [3,2-c]2' phenylpyrazole and the fiuoro-derivative thereof; and6,16a-dimethyl-9a-fluoro- 11B,l8-oxido-4,6-pregnadiene 17a,18,21 triol20 one- [3 ,2-c] -2'-p-fluorophenylpyrazole.

The 17a-hydroxyaldosterone's of my invention are conveniently preparedvia my process preferably from the 17a,20;20,2l-bis-methylenedioxyderivatives of the corresponding 1lfi-hydroxy-l8-oXimino-corticoids(III) which upon treatment with nitrous acid, are converted to the115,18 oxide-18,21-mono-methylenedioxy-intermediates (IV). Treatment ofthe mono-methylenedioxy intermediates (IV) under acidic hydrolyticconditions, e.g., with sulfuric acid in aqueous dioXan, in the cold(preferably around 0 C.) or with acetic acid-acetic anhydride/47%hydriodic acid yields, in turn, an 11/3,18;18,21-bis-oxido intermediate(V). Perchloric acid'catalyzed acylation of the bis-oxido intermediate(V) will yield directly a 17,18, 21-tri-alkanoate (Ia), i.e., al7d-hydroxyaldosterone of this invention, e.g., a composition of FormulaI'wherin R, R and R are lower alkanoyl, which upon mild alkalinehydrolysis will yield the corresponding l7a-hydroxyaldosterone (Ib)wherein R, R and R" equal hydrogen.

A reaction scheme exemplifying my process is shown below with the C andD rings only of the steroid nucleus being shown, the A and B rings andthe moieties A, X and R may be as defined by Formulae I and II:

"ice

I 0- O i O 93H: N H (I;

c l/\ MA HNO, -wa acidic i V hydrolysis (111) Y (1v o-- on, on" onion OCI =0 O--G :0 -OH ---OR' 01110 c A M A peracidri W A acylation V (V)medmm Y (Ia) and l (Ila) i CHiOH O,-C 41:0 i/\ ""5011 (Ib) and (H71) Inthe structural formulae in this specification, the use of a wavy line(NW such as shown at C-16 in the formulae above, indicates that both the16(1- and 16,8- isomers are thereby indicated.

In a typical reaction sequence exemplifying my process, the-18-oximino-17a,20;20,2l-bis-methylenedioxy derivative of prednisolone(i.e.,17u,20;20,2l-bis-methylenedioxy-l8oximino-l,4-pregnadiene-11[3-ol3-0ne)which is an intermediate of partial Formula III wherein A and X arehydrogen, is reacted with nitrous acid (i.e., acetic acid plus 5%aqueous sodium nitrite) to form 11 3,18- oxido 18,21 mono methylenedioxy1,4 pregnadienc-17a-ol-3,20-dione (IV). Acidic hydrolysis of IV with amineral acid in an aqueous medium such as by means of concentratedsulfuric acid in aqueous dioxan at 0 C. yields the bis-oxidointermediate (V), i.e., 11,6, 18;18,21 bis oxido 1,4 pregnadiene 17oz ol3, -dione which, in turn, upon reaction with aqueous perchloric acid inadmixture with acetic acid/acetic anhydride yields the triacetate (Ia orHa), i.e., 17a-hydroxyl-dehydroaldosterone triac'etate (i.e., 113,l8-oxido-1,4- pregnadiene-17a,l8,2l-triol-3,20-dione triacetate) whichis convertible to the corresponding triol, 17a-hydroxy-1-dehydroaldosterone (Ib or IIb), under mild alkaline conditions, such aswith dilute aqueous sodium hydroxide.

In the conversion of the bis-oxido intermediate V to an aldosterone17,18,21-tri-ester (Ia or IIa), by substituting other alkanoicacid/anhydride mixtures, e.g., propionic acid/propionic anhydride, foracetic acid/acetic anhydride, there is obtained the correspondingtri-alkanoate, e.g., 17a-hydroxy-l-dehydroaldosterone tripropionate.

Similarly, a [3,2-c]-pyrazole-18-oximino intermediate of partial FormulaIII is transformable via my process to the corresponding 11-l8-hemiacetal of Formula II. Thus, 16a methyl l7oz,20;20,21 bismethylenedioxy- 18 oximino 4 pregnene 11 8 ol [3,2 c] 2'-p-fluorophenylpyrazole (an intermediate of partial Formula IH wherein Xis hydrogen and A is a-methyl) upon reaction with nitrous acid istransformed to 16- methyl 115,18 oxido 18,21 mono methylenedioxy- 4pregnene -17oc ol 20 one [3,2 c] 2' pfluorophenylpyrazole (IV) which,upon acid hydrolysis with sulfuric acidin dioxan, yields 'the bis-oxidointermediate (V), 16a-methyl-l1,8,18;l8,21-bis-oxido-4-pregnene 170: ol20'- one [3,2 c] 2' p fluorophenylpyrazole which, in turn, upon reactionwith aqueous perchloric acid yields the triacetate (Ila), i.e.,16ozmethyl 1113,18 oxido 4 pregnene 17 ol 20-one-[3,2-c]-2'-p-flu0rophenylpyrazole triacetate, convertible to thecorresponding triol under mild alkaline conditions.

In those instances wherein X is halogen, e.g., fluorine, acidichydrolysis of the l1p,18-oxido-18,2l-mono-methylenedioxy intermediate IVto the 11,3,18;18,21-bis-oxido intermediate V is effected by an aceticacid-acetic anhydride-aqueous hydriodic acid mixture. Thus, for example,9oz fluoro 16a methyl 115,18 oxido 18, 21 mono methylenedioxy 1,4pregnadiene 3,20- dione (IV) (prepared by the action of nitrous acid on90: fluoro 16oz methyl 18 oximino 17a,20;20, 21 bis methylenedioxy 1,4pregnadiene 1119 ol- 3-one (HI)) upon treatment with hydriodic acid inacetic acid/acetic anhydride yields 9a-fluoro-16a-methyl-11/8, 18;18,21bis oxido 1,4 pregnadiene 17a ol 3, 20-dione (V).

Alternatively, in those instances when X is halogen, e.g., fluorine, the115,18-oxido-18,21-mono-methylenedioxy intermediate (IV), is convertibledirectly to a 170:, 18,21-triol (Ib or 11b) of my invention withoutisolation of the bis-oxido intermediate V by means of treatment withsulfuric acidin aqueous dioxan at temperatures in the range of 20-100C., preferably about 7580 C. Thus, for example,9a-fluoro-11,6,18-oxido-18,21-monomethylenedioxy-4-pregnene-17a-ol-3-one(prepared by 4 the action of nitrous acid on 9a-fluoro-18-oximino-17u,20;20,21 bis methylenedioxy 4 4 pregnene ol-3-one) upon treatment withsulfuric acid in aqueous dioxan at 75-80 C., is converted directly to9m-fluorol7a-hydroxyaldosterone, a compound of Formula I. In a similarmanner, 9oc-fluoro-1lfl,l8-oxido-18,2l-monomethylenedioxy 1,4pregnadiene 17a ol 3,20- dione, upon reaction with aqueous dioxan andsulfuric acid at 75 C., is converted directly to9oc-flllOI'O-17ahydroxy-l-dehydroaldosterone.

It is thus apparent from the foregoing that in the novel processdescribed hereinabove, necessary intermediates are the18-oximino-17a,20;20,2l-bis-methylenedioxy-l1B- ol-3-ones (III), the11B,18-oxido-18,21-mono-methylenedioxy derivatives (IV), and the11,8,18;18,21-bis-oxido compounds (V).

The l-dehydroaldosterone derivatives of Formula I, e.g.,l-dehydro-17a-hydroxyaldosterone, ,are prepared from the correspondingl-dehydro corticoid, e.g., prednisolone, by my process as describedhereinabove. Alternatively, ti -dehydrogenation of the correspondingaldosterone (e.g., 17a-hydroxyaldosterone) by known microbiologicalmethods utilizing organisms such as Corynebacterium simplex (ATCC 6946)or via chemical techniques, such as those utilizing selenium dioxide ordicyanodichloroquinone, will yield a 17a-hydroxy-1-dehydroaldosterone ofmy invention.

The 6-dehydroand l,6-bis-dehydroaldosterone derivatives of Formula I,e.g., 6-dehydro-17u-hydroxyaldosterone and1,6-bis-dehydro-17a-hydroxyald0sterone, are prepared from thecorresponding 6-dehydroand 1,6- bis-dehydro-A corticoid, e.g.,6-dehydro-hydrocortisone and 1,6-bis-dehydro-hydrocortisone, by myprocess as exemplified in Examples 10 and 12. Alternatively, Adehydrogenation of the corresponding aldosterone, e.g.,l7u-hydroxyaldosterone, by known procedures, such as that utilizingchloranil in refluxing xylene, or by bromination followed bydehydro-bromination in refluxing collidine will yield the 6-dehydro and1,6-bis-dehydroaldosterones of my invention.

Similarly, the 6-dehydro analogs of the17a-hydroxyaldosterone-[3,2-c]-pyrazoles of Formula II, are convenientlyprepared from the corresponding 4,6-pregnadiene-[3,2-cJ-pyrazoles by myprocess as described hereinabove and in Example 13 or, alternatively, a[3,2-c]- pyrazole derivative of 17a-hydroxyaldosterone, e.g., 16ozmethyl 4 pregnene 1711,21 diol 20 one- [3,2-c] -2-phenylpyrazole, upontreatment with chloranil in refluxing xylene according to knownprocedures, will yield the corresponding A -analog of Formula II, e.g.,16cc methyl 4,6 pregnadiene 1711,21 diol 20- one- [3,2-c]-2'-phenylpyrazole.

The l lfi-hydroxy-l7oz,20;20,21bis-methylenedioxy-l8-oximino-4-pregnenes of Formula III, necessary intermediates in theprocesses of this invention, are conveniently prepared via theultraviolet light photolysis of the ll-nitrite ester of thecorresponding 11/3-hydroxy-18-unsubstituted-17,20;20,2l-bis-methylenedioxy corticoid derivativeutilizing procedures similar to those described in the copending US.applications of Derek Barton, Serial No. 95,490, filed March 14, 1961(continuationin-part of Serial No. 19,444, filed April 4, 1960, nowabandoned) and Serial No. 113,086, filed May 29, 1961, of which theinstant application is a continuation-in-part.

The 11;8-hydroxy-l8 unsubstituted :,20;20,21bi$-methylenedioxy-4-pregnenes having a [3,2-c]-pyrazole function, e.g.,9u-fiuoro 16a methyl 1 ,7u,20;20,21-'bismethylenedioxy-4-pregnene 115 ol[3,2-c]-2'-p-fluoro phenylpyrazole, are conveniently prepared from thecorresponding A -3-keto corticoid, e.g.,9a-fluoro-16a-methylhydrocortisone, via procedures known in the art. Forexample, 9a-tluoro-16a-methylhydrocortisone, after conversion in knownmanner to the corresponding 17a,20;20, 2l-bis-methylenedioxy derivative,is treated with ethyl formate and sodium hydride in benzene to give thecorresponding Z-hydroxymethylene derivative, e.g.,2-hydroxymethylene-9u-fluoro 16a-methyl-l7a,20;20,2l-bis-methylenedioxy-4-pregnene-llfl-ol-3-one, which, when refluxed withan ethanolic solution of p-fluorophenylhydrazine, yields the desired1LB-hydroxy-lS-unsubstituted-[3,2-c1- pyrazole intermediate, e.'g.,90L-flHOIO-16a-Il'l6lZhYl-17oz,20; 20,21-bismethylenedioxy-4-pregnene-1l,B-0l-[3,2-c]-2-pfluorophenylpyrazole.Condensation with other hydrazines, i.e., phenylhydrazine, will yieldthe corresponding [3,2-c]-pyrazole, e.g., 9u-fluoro 161xmethyl-17a,20;20, 2l-bis-methylenedioxy-4-pregnene-1 1,6-01- [3,2-c]-2'- phenylpyrazole.

Alternatively, the pyrazole function can be introduced into the17a-hydroxyaldosterone molecule via procedures similar to those justdescribed. Thus, l7a-hydroxyaldosterone triacetate (prepared as inExample 4) upon treat ment with ethyl formate and sodium hydridefollowed by condensation of the resulting 2-hydroxymethylenederivativewith p-fiuorophenyl-hydrazine, for example, and subsequentmild alkaline hydrolysis of any remaining ester group will yield a[3,2-c]-pyrazole of Formula II, 115,18- oXido-4-pregnene-17a,18,2l-triol[3,2-c]-2'-p-fluorophen ylpyrazole.

In general, to prepare 18-OXllI1lI10-17a,20;20,21-bl5 methylenedioxyintermediates (III), a pregnane having a cortical side chain, e.g.,9a-fluoro-16a-methyl-1,4-pregnadiene-l'lfl,17a,21-triol-3,20'dione and9a-fiuoro-l6a-methyl-4-pregnene-llB,17a,21-triol-20-one[3,2-c]-2'-p-fluorophenylpyrazole, is first converted to thecorresponding bismet-hylenedioxy (also written as BMD) derivativeutilizing known techniques, such as with formaldehyde in chloroform andconcentrated hydrochloric acid. The resulting BMD-derivative, e.g.,9a-fiuoro- 16a-metl1yl-17a,20;20, 21-bis-methylenedioxy-l,4pregnadiene-l -ol-3-one and 9a-fluoro-16a-methyl-17a,20 ;20,21bis-methylenedioxylpregnene-l l S-ol- [3,2-c] -2-p-fluorophenylpyrazole,is then converted to the corresponding nitrite ester by reaction with anexcess of nitrosyl chloride in pyridine in the cold. Photolysis of theresultant ll-nitrite ester is then efiected preferably by irradiating atoluene solution of the nitrite ester under a blanket of nitrogen atabout C. with ultraviolet light supplied by a Hanovia high-pressure,mercury arc lamp with a Pyrex sleeve. Isolation of the desired18-oximino intermediate (III), e.g., 9ot-fl110l'O-16w methyl-1711,20;20,21-bis methylenedioxy-l8-oximino-l,4- pregnadiene-1lB-ol-3-one and9a-fluoro-l6u-rnethyl-l7a,20;20,21-bis-methylenedioxy18-oxirnino-4-pregnene-l1pol-[3,2-c]-2'-p-fluorophenylpyrazole, is then usually effected bymeans of chromatographic techniques well known in the art.

The 17a-hydroxyaldosterone derivatives of Formulae I and II arepreferably prepared by my process as described hereinabove whereby an18-OXlmln0l7oc,20;20,21-bl5 methylenedioxy-4-pregnene-11,6-ol-3-one ofFormula III is treated with nitrous acid followed by controlled acidhydrolysis of the 11,8,18-oxido-18,21-mono-methylenedioxy-4-pregnene(IV) thereby formed. My invention is not to be construed as limited tothe preparation of the specific compounds described herein. Anyll-hydroxy steroid also having an 18-oximino group and a 17u,20;20,ZI-bis-methylenedioxy function may be converted by the preferredembodiment of my process to the corresponding l7a-l1ydroxyaldosteronederivative.

The process outlined hereinabove is the preferred method of preparingthe compounds of Formulae I and II; however, rny 17 a-hydroxyaldosteronederivatives are also prepared via the nitrous acid treatment ofllB-hydroxy-IS- oximino-4-pregnene corticoid intermediates having anester function at C-2l or a ketal function at C-20, which intermediatesare prepared by procedures known in the art. Thus, hydrocortisone21-acetate ll-nitrite in toluene is photolyzed with ultraviolet light togive 18-oximinohydrocortisone 21-acetate which, when treated with sodiumnitrite in acetic acid, will yield directly 17 a-hydroxyaldosterone21-acetate. Alternatively, the 3,2-bis-ethylene ketal derivative ofhydrocortisone ll-nitrite, upon photolysis in toluene with ultravioletlight, yields the 320- bis-ethylene ketal of 18-oximino-hydrocortisonewhich, when treated with sodium nitrite in acetic acid, yields the3,20-bis-ethylene ketal of 17a-hydroxyaldosterone 21-acetate, i.e.,3,20-bis-ethylenedioxy-1 l/3-18-oxido-5-pregnenel7a,l8,2ltll0l2l-acetate. Treatment with sulfuric acid in aqueous dioxan then yields abis-oxido intermediate (V), i.e.,11,8,18;l8,2'1-bis-oxido-4-pregnene-17a-ol-3,20 dione, which isconvertible to 17a-hydroxyaldosterone and the tri-lower alkanoate estersthereof by procedures described hereinabove.

By utilizing as starting compounds naturally derived compounds ofabsolute configuration such as are described herein, e.g.,hydrocortisone, 9u-fluoro-l6B-methylprednisolone, etc., my novel processadvantageously prepares only the d-form of 17a-hydroxyaldosteronederivatives.

The d-17a-hydroxyaldosterone derivatives such as those of Formulae I andII are pharmaceutically active, inducing a decrease in the number ofcirculating eosinophils without inducing a negative nitrogen balance; infact, sometimes promoting a positive nitrogen balance. Additionally, insharp contrast to d-aldosterone, the substituted aldosterones of thisinvention show a minimum of sodium retaining properties.

In general, the substituted aldosterone derivatives such as those ofFormulae I and II are valuable as anti-inflammatory agents which, sincethey do not induce a nitrogen loss such as occurs withthe-administration of corticoids such as cortisone, predni-sone,dexamethasone, and the like, do not cause undesirable side effectsassociated with nitrogen imbalance such as purpura, osteopetrosis, andthe like.

The substituted aldosterone-s such as those of Formulae I and II arealso valuable as anabolic agents and, thus, are useful in promotingweight gain for those in debilitated states, for the relief of pain inthe treatment of osteoporosis and arthritis, and in promoting tissuerepair and. increasing vitality to those convalescing or in geriatricstates.

The preferred species of this invention are the 17:1.-hydr-oxy-l-dehydroaldosterone derivatives, and particularly,9a-fluoro-16a-methyl-17a-hydroxy-l-dehydroaldosterone. These compoundsare valuable as anti-inflammatory agents and are particularly useful intopical pharmaceutical forms for use in ailments such. as Lupuseryzhematosz's and other skin dermatoses, as well as in skin dermatitisand pemphigus.

The invention is described more fully in the examples which follow.These examples are set forth by way of illustration only, and it isunderstood that the invention is not to be construed as limited to thedetails contained therein as many modifications in materials and methodswill be apparent from the disclosure to those skilled in the art. Theinvention is to be limited only by the scope of the appended claims.

Example 1 .1 7a-hydr0xy-1-dehydroaldoster0ne (1113,, 18-0xid0-1,4-pregnadiene-1 7a,] 8,21-tri0l-3,20-r5i0ne) A. 17a,20;20,21-bismethylenedioxy 1,4-pregnadiene- 1lfi-0l-3-0ne 11-nitrite.Treat asolution of 3.8 g. of 17a,20;20,2l-bis-methylenedioxy-1,4 pregnadiene1-1/3- ol-3-one in ml. of pyridine at --20 C. with nitrosyl chloride gasuntil an orange color persists. Allow the solution to warm to roomtemperture, dilute with Water, and extract with methylene chloride. Washthe combined extracts with water, dry over sodium sulfate, and evaporatethe solvent in vacuo to a residue comprising17a,20;20,2l-bis-methylenedioxy h 1,4 pregnadiene 1113- ol-3-onell-nitrite. Purify by crystallization from methylene chloride-methanol.M.P. 188 -190 C.

B. 17a,20;20,21 bis methylenedioxy 18. oximino-1,4-pregnadiene-11B-0l-3-0ne.By means of a Hanovia 500 watt highpressure mercury arc lamp, irradiate for 2 hours a solution of 5 g. of17a, 20;20,2l-bisamethyl- 7 enedioxy-l,4-pregnadiene-11B-ol-3-onell-nitrite in 200 ml. of toluene containing a trace of pyridine placedinside a water cooled Pyrex immersion well. Maintain slight agitation ofthe solution by means of a stream of pure nitrogen and keep the reactiontemperature around 20 C. by regulating the temperature of the coolingwater. Without further treatment, chromatograph the irradiated solutionover 100 g. of alumina eluting with methylene chloride containingincreasing proportions of methanol. Combine the later, like fractionsand evaporate to a residue substantially of17u,20;20,2l-bis-methylenedioxy 18-oximino-1,4-pregnadiene-11B-ol-3-one.Purify by crystallization from ethyl acetate-hexane. M.P. 270-274" C.

C. 115,18-x1'd0 18,21 mono methylenedioxy 1,4- pregnadiene-17a-0l-3,20-di0ne.To 1 g. of 17a,20;20,21- bis-methylenedioxy-l8-oximino 1,4pregnadiene 11,S- ol-3-one in 34 ml. of acetic acid at 50 C., add 24 ml.of 5% aqueous sodium nitrite. Allow the solution to stand at roomtemperature for 1.5 minutes (Color change: yellow-blue-green-yellow).Pour the reaction mixture into water and extract several times withmethylene chloride. Wash the combined extracts with aqueous sodiumbicarbonate, dry over sodium sulfate, and evaporate in vacuo to aresidue of substantially 11B,18-oxido-18,21- mono methylenedioxy 1,4pregnadiene 17a ol 3, -dione. Purify by chromatography over 20 g. ofalumina with methylene chloride containing increasing portions ofmethanol. Evaporate the combined fractions in vacuo and crystallize theresultant residue from acetonehexane and then from methylenedichloride-methanol. M.P. 2ll-2l6 C.

D. 11B,18;18,21 bis oxido 1,4 pregnadiene 17aol 3,20-di0 ne.T0 mg. ofl1p3,18-oxido-18,2l-monomethylenedioxy-l,4-pregnadiene-17a-ol-3,20-dionein 3 ml. of dioxan and 7 ml. of water at 0 0., add with stirring 0.6 ml.of concentrated sulfuric acid. Allow the solution to warm to roomtemperature and then heat on a steam bath under nitrogen for two hours.Add water and extract with methylene chloride. Combine the methylenechloride extracts and concentrate in vacuo to a residue of substantially115,18;18,21-bis-oxido-l,4- pregnadieneql7a-ol-3,ZO-dione. Purify bycrystallizing several times from acetone-hexane. M.P. 235-244 C. E.115,18 oxido 1,4 pregnadiene 17a,18,21 triol- 3,20 dione triacetate.To asolution of 1 g. of 11/3, 18;18,21 bis oxido 1,4 pregnadiene 17a ol 3,20-dione in 100 ml. of acetic acid and ml. of acetic anhydride cooled to5 C., add dropwise with vigorous stirring 12 ml. of aqueous perchloricacid. Keep the solution at 5 C. for 2 hours; then pour into ice water,neutralize with aqueous ammonia, and extract with methylene chloride.Combine the methylene chloride extracts and concentrate in vacuo to aresidue of substantially 11B,18-oxido-l,4-pregnadiene-l7a,18,21-triol3,20 dione triacetate. Purify by crystallization from ethylacetatehexane. M.P. 235-240 C.

F. 115,18 oxido 1,4 pregnadiene 17a,]8,21-triol- 3,20-di0ne.-To asolution of 126 mg. of 11,8,18-oxido- 1,4-pregnadiene 17oz,l8,21 triol3,20 h dione triacetate in 30 ml. of methanol at 0 C. add 2.8 ml. of 0.1aqueous sodium hydroxide and stir the solution at 0 C. under nitrogenfor one hour. Dilute with ml. of water containing 2 drops of aceticacid, and extract the reaction mixture several times with methylenechloride. Combine the methylene chloride extracts and evaporate in vacuoto a residue of substantially 1lfi,18-oxido-1,4- pregnadiene 17a,l8,21-triol-3,20-dione. Purify by crystallizationfrom ethylacetate-methanol. M.P. 205210 C.

Example 2 .-9u. fluoro 17cc hydroxyaldosterone (9ozfluoro11fi-18-0xido-0xido 4 pregne ne ]7oc,18,21-

' triol-3,20-di0ne) A." 9.; fluoro 17,20;20,21 bis methylenedioxy 4-pregnene 11 {3 ol 3 one 11 -Initrite.-Treat 25 g. of

' one.

8 9oz fluoro 17oz,20;20,21 bis methylenedioxy 4 pregnene-llfi-ol-3-onein pyridine with nitrosyl chloride in a manner similar to that decribedin Example 1A. Isolate the resultant product in the described manner togive 9a-fluoro-l7ot,20;20,21-bis methylenedioxy 4 pregnene- 11,8-01-3-0ne ll-nitrite.

B. Qu-fluoro 18 oximino 17oz,20;20,21 bis methylenedioxy 4 pregnene 11f?0l 3 0ne.In a manner similar to that described in Example 1B, irradiatea solution of 9a-fluoro-17a,20;20,21bis-methylenedioxy-4-pregnenel1fi-ol-3-one ll-nitrite (prepared in Example 2A) in 1.3 l. oftoluene containing a trace of pyridine for 1.5 hours at 5-10 C. undernitrogen using a 500 watt Hanovia lamp. Chromatograph the irradiatedsolution over Florisil eluting with (4:5) benzene-methylene chloride.Combine the eluates and evaporate in vacuo to a residue of substantially9w-fluoro-18-oximino-17a, 20;20,21-bis-methylenedioxy-4-pregnene ol3-one. Use without further purification in the following procedure 2 C.

C. 9a-flu0r0-115,18-0xid0-18,21-m0n0-methylenedi0xy-4-pregnene-17a-0l-3,20-di0ne.To 2.5 g. of 9a-fiuoro-18- oximino17e,20;20,21 bis-methylenedioxy 4-pregnene- 11fi-ol-3-one in 200 ml. of75% aqueous acetic acid at 2 C., add 25 ml. of water containing 3.75 g.of sodium nitrite. Allow the solution to stand at room temperature for20 minutes; then extract with methylene chloride. Evaporate the combinedmethylene chloride extracts to a residue and chromatograph the residueover Florisil in methylene chloride. Concentrate the combined eluates toa residue of substantially 9oc-flHOIO-11fi,18-OXid0-18,21-mono-methylenedioxy-4-pregnene-17a-ol-3,20-dione. Purify bycrystallization from ethyl acetate-hexane. M.P. 234-260 C. After severalrecrystallizations M.P. 252- 265 C.

D. 9a-flu0r0-1 1 5,1 8-oxido-4-pregnene-1 7a,] 8,21-tri0l-3,20-di0ne.Heat in a stream of nitrogen for one hour at 75-80 C. asolution of mg. of 9u-fluoro-llfl,l8- oxido18,2l-mono-methylenedioxy-4-pregnene-1704-01-3, 20-dione in 9 ml. ofdioxan and 20 ml. of water containing 1.8 ml. of concentrated sulfuricacid. Dilute with water and extract with methylene chloride. Evaporatethe combined extracts to a residue substantially of 9afluoro-l 13,18-oxido-4-pregnene-l7a,18,21-triol 3,20 di- Purify by crystallizationfrom ethyl acetate-methanol. .M.P. 210-218" C.

A. 9u-fluor0-1 1 8,18-0xid0-18,21-m0n0-methylenedi0xy-1,4-pregnadiene-17a-0l-3,20-di0ne.--To a solution of 2 g. of 9a-fluoro-115, 18-oxido- 18 ,21-mon0-methylenedioxy-4- pregnene-17a-ol-3,20-dione(the compound of Example 2C) in 100 ml. of butanol containing 0.24 ml.of pyridine, add 810 mg. of selenium dioxide. Reflux under nitrogen for72 hours. Distill the solvent in vacuo, dissolve the resultant residuein methylene chloride, and filter through Supercel. Wash the filteredsolution with aqueous sodium bicarbonate, ammonium sulphide, 2 N aqueousammonia, water and, finally, saturated sodium chloride solution.Chromatograph the washed methylene chloride solution over 50 g. ofalumina, utilizing methylene chloride containing increasing amounts ofmethanol. Combine like fractions and concentrate in vacuo to a residueof substantially 9a-fiLI01'O-l 1/8, 18-oxido-l8,2l-mono-methylenedioxy-1,4-pregnadiene-17z-ol-3,20-dione. Purify byfurther chromatography and crystallization from ethyl acetate-hexane.M.P. 239253 C.

B. 90: fluoro-11,8,18-0xid0-1,4-pregnadiene-17a,18,21-triol-3,20-dione.-Heat a solution of 180 mg. of 9a-fil10l0- 115,18 oxido18,2l-mono-methylenedioxy-1,4-pregnadiene-17a-ol-3,20-dione in 9 ml. ofdioxan and 20 ml. of water containing 1.8 ml. of concentrated sulfuricacid under an atmosphere of nitrogen at 80 C. for 1.8 hours.

Dilute with water and extract with methylene chloride. Evaporate thecombined extracts to a residue of substantially 9a fluoro-ll5,18-oxido-1,4-pregnadiene-l7a,18,2 1- triol-3,20-dione. Purify bycrystallization from acetonemethanol. M.P. 203-2l6 C. After severalrecrystallizations, M.P. 205213 C.

Example 4.17oz hydroxyaldoster ne(115,18 oxido-4- pregnene-I7a,18,21-tri0l-3,20-di0ne) A.17a,20;20,21-bis-methylenedioxy-4-pregnene-1Ifi-ol- 3-one.-To 100 g. offinely powdered hydrocortisone (4- pregnened1/3,17a,21-triol-3,20-dione)suspended in 4 l. of chloroform and 1 1. of 37% formaldehyde, add atroom temperature with stirring 1 1. of concentrated hydrochloric acid.Stir for about 40 minutes; then separate the layers. Wash the chloroformlayer with water, dry over sodium sulfate and chomatograph over 2 kg. ofalumina, eluting with methylene chloride containing increasing amountsof methanol. Combine the early, like fractions and evaporate to aresidue of substantially 17ca,20;20,21-bis-methylene-dioxy-4-pregnene-11B-ol-3-one. Purify by crystallizationfrom ethyl acetate. Combine the like, late fractions and evaporate invacuo to a residue and crystallize several times from ethyl acetate toobtain llfl-(hydroxymethylene)oxy 17a,20;20,21 bis-methylenedioxy-4-pregnene-3-one. Conversion of this compound to the compound of thisexample, i.e., 17u,20;20,21-bis-methylenedioxy-4-pregnene-11,9,01-3-one,is effected either by refluxing the 1lfl-(hydroxymethylene)oxyderivative in acetic acid under nitrogen for 5 minutes or by heating itat 200 C. in an open tube for about 2 minutes, during which time thecompound melts with elfervescence and then resolidifies.

B. J 7a,20;20,21-bis-methylenedioxy-4-pregnene-1 1 8-01- 3-0ne11-nitrite.Treat 27.5 g. of17a,20;20,2l-bis-methylenedioxy-4-pregnene-11,8-ol-3-one in 200 ml. ofpyridine at room temperature with nitrosyl chloride gas until an orangecolor persists. Cautiously dilute with water; filter the resultantprecipitate substantially of 17u,20;20,21- bis methylenedioxy4-pregnene-11 8-ol-3-one 11-nitrite. Purify by crystallization frommethylene chloride-hexane. M.P. 170-172" C.

C. 17a,20;20,21-bis-methylenedioxy-18-oximino-4-pregnene-115-0l-3-0ne.-In amanner similar to that described in Example 1B, irradiate a solution of6.4 g. of 17u,20;20, 21-bis-methylenedioxy-4-pregnene-11B-ol-3-one in200 ml. of toluene at 5 C. for 90 minutes. Allow the irradiated solutionto stand overnight at 5 C.; then chromatograph over 200 g. of alumina,eluting with methylene chloride containing increasing portions ofmethanol. Combine the like, late fractions and concentrate to a residueof substantially of 17a,20;20,21- bis-methylenedioxy-l8-oximino-4-pregnene-llB-ol-S-one. Purify by crystallization from ethyl acetate.M.P. 220-229" C.

D. 11,8,18 oxido 18,21 mono methylenedioxy 4-pregnene-J7oz-0l-3,20-di0ne.ln a manner similar to that described inExample 1C, treat 6.33 g. of 17a,20;20,21- bis methylenedioxy 18oximino-4-pre-gnene-116-01-3- one in 180 ml. of acetic acid with 60 ml.of 5% aqueous sodium nitrate (color change: blue-green-yellow). Isolatethe resultant product in the described manner to obtain11,8,18-oxido-18,21-mono-methylenedioxy-4-pregnene-17a-ol-3,20-dione.Purify by chromatography over 380 g. of alumina, eluting with methylenechloride containing increasing portions of methanol. Combine the eluatescontaining up to 1% methanol and evaporate in vacuo to a residue.Crystallize the residue from ethyl acetate. M.P. 194-216 C. Afterseveral recrystallizations from ethyl acetate-hexane, M.P. 220236 C.

E. 11fi,18;18,21 bis oxido 4 pregnene 17oz ol- 3,Z0-dione.ln a mannersimilar to that described in Example 1D, to 500 mg. of11/8,18-oxido-18,21-monomethylenedioxy-4-pregnene-l7a-'ol-3,20-dione in6 ml. of dioxane and 14 ml. of water at 0 C. under a blanket ofnitrogen, add 1.2 ml. of concentrated sulfuric acid and 10 heat on asteam bath for minutes. Add water and extract with methylene chloride.Combine the methylene chloride extracts and concentrate in vacuo to aresidue of substantially 11a,18;l8,21 bis oxido 4 pregnene-17u-ol-3,20-dione. Purify by crystallization from ethyl acetate. M.P.201-210 C.

F. 1113,18 oxido 4 pregnene 17a,18,21 trial 3, 20-di0ne triacetate.To880 mg. of 11p, 18;18,21-bisoxido-4-pregnene-17u-ol-3,20-dione in 92 ml.of glacial acetic acid and 8.75 ml. of acetic anhydride together with1.05 ml. of ethyl acetate at 13 C. with stirring, add dropwise over afive-minute interval 0.78 ml. of 70% perchloric acid. Continue stirringfor 55 minutes at 14-15 C. Pour the solution rapidly onto 1400 ml. ofice water containing 95 ml. of 10 N ammonium hydroxide. Allow thereaction mixture to stand for 20 minutes, filter the suspension, anddiscard the solid. Extract the filtrate with methylene chloride andevaporate the combined extracts in vacuo to a residue of substantially1lfi,18-oxido- 4-pregnene-17a,18,21-triol-3,20-dione triacetate. Purifyby several crystallizations from acetone-hexane. M.P. 114-l24 C.

G. 1113,18 oxido 4 pregnene 1711,1821 triol 3, 20-di0ne.ln a mannersimilar to that described in Example IF, treat 602 mg. of l18,l8-oxido-4-pregnene-l7a, 18,21-triol-3,20-dione triacetate in methanolat 0 C. under nitrogen with 13.2 ml. of 0.1 N aqueous sodium hydroxide.Isolate the resultant product in the described manner to obtain11,8,18-oxido-4-pregnene-l7u,18,21- triol-3,20-dione. Purify by severalcrystallizations from methanol. M.P. 215-220" C.

The compound of this example, i.e., 11,8,18-oxido-4-pregnene-17a,18,21-triol-3,20-dione triacetate, in tertiarybutanolcontaining pyridine, upon treatment with selenium dioxide in a mannersimilar to that described in Example 3A, is converted to thecorresponding l-dehydro analog, i.e.,11,8,18-oxido-1,4-pregnadiene-17u,l8,21-triol-3,20-dione triacetate (thecompound of Example 1E).

Example 5.9u fluoro 1604 q methyl 1 dehydroaldster0ne(9z fluoro 11,8,18oxido 16oz methyl- 1,4 pregnadiene 17a,18,21 trial 3,20 dione) A. 904fluoro 16oz methyl 17oc,20:20,21 bis methylenedioxgy 1,4 pregnadiene11}? ol 3 one 11- nitrite.In a manner similar to that described inExample lA, treat 17.5 g. of 9a-fluoro-16a-rnethyl-l7u,20; 20,21bis-methylene-dioxy 1,4 pregnadiene-llfi-ol-Iione in pyridine withnitrosyl chloride at room temperature. Isolate the resultant product inthe described manner to obtain9u-fiuoro-16a-methyl-l7a,20;20,2l-bis-methylenedioxy-1,4-pregnadiene-11p-ol-3-onell-nitrite. This product is used without further purification inprocedure 5B immediately following.

B. 90: fluoro 16a methyl 18 oximino 17a,20;20, 21 bis methylenediox 1,4pregnadiene 115 ol- 3-one.Dissolve the9a-fluoro-16u-methyl-17a,20;20,21- bis -methylenedioxy 1,4 pregnadiene11,8 ol 3 one ll-nitrite prepared in Example 5A in 650 ml. of toluenecontaining a trace of pyridine and photolyze at 25 C. under nitrogen for2.6 hours in the manner of Example 1B. Isolate the resultant product inthe described manner to obtain 9a-fluoro-16u-methyl-18=oximino-17a,20;20,21 bis methylenedioxy 1,4 pregnadiene 11B ol- 3-one. Purify bycrystallization from acetone-hexane. M.P. 288-297 C.

C. 90: fluOro 1600 methyl 115,18 xido 18,21- mono meth lenedioxy 1,4pregnadiene 17a ol 3, 20-dione.In a manner similar to that described inExample lC, to a solution of 2 g. of 9u-fluoro-16u-methyl- 18 'oximino17a,20;20,21 bis methylenedioxy 1,4- pregnadiene-1l 3-ol-3-0ne in ml. ofglacial acetic acid and 50 ml. of water at 2 C., add 3.75 g. of sodiumnitrite in 25 ml. of water over a period of 15 minutes allowing thesolution temperature to rise to room temperature. Isolate the resultantproduct in the described manner to obtain 90: fluoro 16a methyl 11,8,18-oxido 18,21 mono methylenedioxy 1,4 pregnadienel7a-ol-3,20-dione. Purifyby chromatography over 50 g. of Florisil, eluting with methylenechloride containing increasing portions of methanol. Combine likefractions and evaporate to a residue. Recrystallize the residue fromethyl acetate. M.P. 243260 C.

D. 90: fluorO 16a methyl 1118,18;18,21 bis-oxida- 1,4 pregnadiene 17a l3,20 di0ne.To 1.55 g. of 9a fiuoro 16a. methyl 115,18 oxido 18,20monomethylenedioxy-1,4-pregnadiene-17a-ol-3,20dione in 60 ml. of glacialacetic acid and 16 ml. of acetic anhydride at C. under nitrogen, addwith stirring 4 ml. of 47% aqueous hydriodic acid. Continue stirring atroom temperature for 15 minutes, dilute with 2% aqueous sodiumthiosulfate and extract with methylene chloride. Combine the methylenechloride extracts, wash with water, and concentrate in vacuo to aresidue. Dissolve this residue in 120 ml. of methanol, add 12 ml. ofwater and 12 ml. of 10% aqueous potassium carbonate, and keep at roomtemperature under nitrogen for minutes. Distill the methanol in vacuoand extract the reaction mixture with methylene chloride. Chromatographthe methylene chloride solution over alumina, eluting with methylenechloride containing increasing portions of methanol. Combine the likefractions and evaporate to a residue of substantially9a-fiuor0-16a-methyl-11/3,l8;18,21-bis-oxido-1,4-pregnadiene-17a-ol-3,20-dione. Purify by several crystallizations fromacetone-hexane. M.P. 267-280 C.

E. 9m fluoro 11 8,18 oxido 16a methyl 1,4- pregnadiene 17u,18,21 triol3,20 dione triacetate. In a manner similar to that described in Example1E, treat 2.3 g.,of 9oc-fll10IO-16a-methYl-11}3,18;18,21-biS-0X-ido-1,4-pregnadiene-17u-ol-3,20-dione in 240 ml. of acetic acid and 150ml. of acetic anhydride at room temperature with stirring with 3 ml. of70% aqueous perchloric acid. Continue stirring for 2.8 hours. Pour thesolution into ice water containing 390 ml. of concentrated aqueousammonia. Isolate by extraction with methylene chloride in the describedmanner and purify by crystallization from acetone-hexane to give9a-fiuoro-11B,18-oxido- 16cc methyl 1,4 pregnadiene 17a,l8,21 triol3,20- dione triacetate. M.P. 258-269 C.

F. 9oz flame-115,18 oxido-16a methyl 1,4pregnadiene-l7a,]8,21-tri0l-3,20-di0ne.ln a manner similar to thatdescribed in Example 1F, stir for minutes at 0 C. under nitrogen asolution of 500 mg. of 9a-fluoro- 11,3,18 oxido 16a methyl 1,4pregnadiene 17oz, 18,21-triol-3,20-dione triacetate in 105 ml. ofmethanol with 13.8 ml. of 0.1 N aqueous sodium hydroxide. tinue stirringfor 45 minutes and isolate the resultant product in the described mannerto give 9a-fluoro-1l;3,l8- oxido 16a methyl 1,4 pregnadiene 17u,18,21triol- 3,20-dime. Purify by several crystallizations fromacetone-hexane-methanol. M.P. 256-265 C.

Example 6,-9-brom0-1701,20;20,21-bis-methylenedi0xy-4-pregnene-11/3-0l-3-0ne A.17oz,20;20,21 bis methylenedioxy 4 pregnene- 11a-0l-3-0ne.To 200 g. of4-pregnene-11a,17u,21-trio1- 3,20-dione in 7 l. of chloroform, add amixture of 1.7 l. of v37% formaldehyde and 1.7 1. of 12 N hydrochloricacid and stir the mixture for one hour. Separate the layers and wash theinorganic layer with chloroform. Wash the combined chloroform extractswith a saturated solution of sodium bicarbonate, dry over sodiumsulfate, and chromatograph over alumina, eluting with methylene chloridecontaining increasing amounts of methanol. Combine the like, earlyfractions and concentrate in vacuo to a residue of substantially17a,20;20,21-bismethylenedioxy-4-pregnene-1la-ol-3-one. Purify bycrystallization from chloroform-ethyl acetate. M.P. 241- 246 C.

Con-

B. 17a,20;20,21 bis methylenedioxy 4,9(11) pregnadiene-3-0ne.To 38.5 g.of 17a,20;20,2l-bis-methylene dioxy-4-pregnene-11a-ol-3-one in 250 ml.of pyridine, add 33 g. of p-toluene-sulfonyl chloride and stir at roomtemperature for 64 hours. Dilute with 3 l. of water and add hydrochloricacid until the reaction solution is at pH 2 or lower. Filter theresultant precipitate, wash with water, and dry at 60 C. in vacuo; thendissolve in 900 ml. of glacial acetic acid containing 36 g. of sodiumacetate. Reflux the reaction mixture for 2.75 hours; then pour onto2.5 1. of slurried ice containing 1040 ml. of 10 N ammonium hydroxide.Filter the resultant precipitate of substantially 17a,2(];20,21-bi$methylenedioxy 4,9(11) pregnadiene 3 one. Purify by crystallization fromacetone-hexane. M.P. 216- 220 C.

C. bromo l7a,20;20,21 bis methylenedioxy- 4-pregnene-1lfi-ol-3-one.-To18 g. of 17u,20;20,21bi$- methylenedioxy-4,9(11)-pregnadiene-3-one in260 ml. of freshly purified dioxan containing 12 ml. of 0.5 N aqueousperchloric acid, add with stirring 5 g. of N-bromoacetamide. Continuestirring and at 15 minute intervals add 2 further portions of 5 g. ofN-bromoacetamide (total 15 g.). Stir for one hour longer; then add 220ml. of 10% aqueous sodium sulfite. Filter the resultant precipitate ofsubstantially 9oz-bI0mO-17a,20;20,2l-biS- methylenedioxy 4 pregnene ol 3one. Purify by crystallization from ethyl acetate-methylenechloridehexane. M.P. 178 C. dec.

Example 7. 90c bromo hydroxyaldosterone (9a bromo 115,18 oxido 4pregnene 17a,18,21- triol-3,20-di0ne) A. 90; bromo l 7a,20;20,21 bismethylenedioxy- 4-pregnene-11/3-ol-3-0ne-11-nitrite.ln a manner similarto that described in Example 1A, treat 8 g. of 9a-bromo-17a,20;20,2l-bis-methylenedioxy 4 pregnene 11p ol- 3-one in 180 ml. ofpyridine with an excess of nitrosyl chloride at room temperature. Dilutethe reaction mixture with ice and water and filter the resultantprecipitate of substantially 9a bromo 17a,20;20,21 bis methylenedioxy 4pregnene 11B o1 3 one 11 nitrite, which is used without furtherpurification in the following procedure 7B.

B. 90: bromo .17oz,20,'20,21 bis methylenedioxy- 18 oximino 4 pregnene11B ol 3 0ne.Dissolve the 9m bromo 17a,20;20,21 bis methylenedioxy 4-pregne'ne-1lB-ol-3-one ll-nitrite prepared in Example 7A in 650 ml. oftoluene containing 0.1 ml. of pyridine. Photolyze the solution for onehour at 0 C. under nitrogen in the manner of Example 1B. Dilute theirradiated solution with 2 l. of methylene chloride and chromatographover 300 g. of Florisil, eluting with methylene chloride containingincreasing portions of methanol. The fraction eluted with methylenechloride containing 2% methanol is evaporated to a residue ofsubstantially 9a-bromo-l7a,20;20,2l-bis-methylenedioxy- 18 oximino 4pregnene 11B ol 3 one. Purify by crystallization from acetone-hexane.M.P. 170 C. dec.

C. 90: bromo 11,8,18 oxido 18,21 mono methylenedioxy 4 pregnene 17a ol3,20 di0ne.In a manner similar to that described in Example 1C, treat950 mg. of 9a-bromo-17a,20;20,2l-bis-methylenedioxy-18-oximino-4-pregnene-11fl-o1-3-one in 70 ml. of glacial acetic acid and15 ml. of water with 1.75 g. of sodium nitrite in 20 ml. of water at 0C. for 25 minutes. Dilute the reaction mixture with 400 ml. of watercontaining 70 ml. of concentrated aqueous ammonia. Extract withmethylene chloride and evaporate the combined extracts in vacuo to aresidue. Chromatograph the residue over Florisil, eluting with methylenechloride containing increasing amounts of methanol. Combine the like,early fractions and evaporate in vacuo to a residue of substantially 90cbromo 1113,18 oxido 18,21 monomethylenedioxy 4 pregnene 17oz o1 3,20dione.

13 Purify by crystallization from acetone-hexane. 180 C. dec.

Combine the like, late fractions and evaporate in vacuo to a residue ofsubstantially 9u-bromo-115,18- oxido- 18 oximino 17x,20;20,21 bismethylenedioxy- 4-pregnene-3-one. Purify bycrystallization fromacetonehexane. M.P. 340 C. dec.

D. 9a bromo 115,18 oxido 4 pregnene 17a, 18,21-tril-3,20-dione.-In amanner similar to that described in Example 2D, treat at 75-80 C. asolution of 90a bromo 115,18 oxido 18,21monomethylenedioxy-4-pregnene-17a-ol-3,20-dione in aqueous dioxan withconcentrated sulfuric acid. Isolate and purify the resultant product inthe described manner to give 9a-bromo- 115,18 oxido 4 pregnene 17a,18,21triol 3,20- dione.

Example 8.9a fluoro 165 methyl 1 dehydroala'osterone(9u fluoro 115,18oxido 165 methyl 1,4- pregnadiene 17a,]8,21 triol 3,20 dione) A. 9ozfluoro 165 methyl 17a,20;20,21-bis-methylenedioxy 1,4 pregnadiene 115 ol3 0ne.In a manner similar to that described in Example 4A, treat 90:fluoro 165 methyl 1,4 pregnadiene 115,l7a,2ltriol 3,20 dione inchloroform with 37% formaldehyde and hydrochloric acid and isolate andpurify the resultant product to give 90: fluoro 165 methyl 17a,20;20,21-

bis methylenedioxy 1,4 pregnadiene 115 ol-3-one.

B. 90: fluoro 165 methyl 17a,20;21 bis methylenedioxy 1,4 pregnadiene115 ol 3-0ne 11-nitrite. In a manner similar to that described inExample 5A, esterify 9a fluoro 165 methyl 17a,20;20,21 bismethylenedioxy1,4 pregnadiene 115 ol 3 one with nitrosyl chloride in pyridine andisolate the resultant product to give 90: fluoro 165 methyll7a,20;20,21- bis-methylenedioxy 1,4 pregnadiene 115 ol 3 one 1l-nitrite.

C. 9oz fluoro 165 methyl 17a,20;20,21-bis-methylenedioxy 18 oximino 1,4-pregnadiene 115-0l-3-0ne.-

In a manner similar to that described in Example 513, irradiate asolution of 9a-fiuoro-165-methyl-17u,20;20,2lbis methylenedioxy 1,4pregnadiene 115 ol 3-one ll-nitrite in toluene containing a trace ofpyridine by means of a Hanovia 500 Watt high-pressure mercury arc lampunder nitrogen and isolate and purify the resultant product in thedescribed manner to give 90: fluoro 165- methyl 17a,20;20,21 bismethylenedioxy-l8-oximino- 1,4-pregnadiene-l l5-ol-3-one.

D. 90: fluoro 165 methyl 115,18 oxido 18,21- mono methylenedioxy 1,4pregnadiene 17a-0l-3,20- di0ne.In a manner similar to that described inExample 5C, treat a solution of 9a-fluoro-165-methy1-17a,20;20,21- bismethylenedioxy 18 oximino 1,4 pregnadiene 115 ol 3 one in acetic acidwith sodium nitrite at Isolate and purify the resultant product in thedescribed manner to give 90: fluoro 165 methyl-115,18- oxido 18,21 monomethylenedioxy 1,4 pregnadiene- 17a-o1-3,20-dione.

E. 9u-flu0ro 165 methyl 115,18;18,21 bis oxido- 1,4 pregnadiene 17a ol3,20 di0ne.In a manner similar to that described in Example 5D, treat asolution of 9a fluoro 165 methyl 115,18 oxido 18,21-mono methylenedioxy1,4 pregnadiene 17a ol-3,20-dione in acetic acid/ acetic anhydride at--20 C. with 47% aqueous hydriodic acid. Isolate and purify theresultant product in the described manner to give 90: fluoro 165- methyl115,18;l8,21 bis oxido 1,4 pregnadienel7a-ol-3,20-dione.

F. 90: fluoro 165 methyl 115,18 oxido 1,4- pregnadiene 17cz,18,21 triol3,20 dione triacetate.- In a manner similar to that described in Example5E, treat a solution of 9a fluoro 165 methyl-1l5,18;18,2lbis oxido 1,4pregnadiene 17 oz ol 3,20 dione in acetic acid/acetic anhydride at 5 C.with 70% aqueous 14 in the described manner to give 9a fluoro 165methyl- 1l5,18 oxido 1,4 pregnadiene l7a,l8,21-trio13,20- dionetriacetate.

G. 90: fluoro 165 methyl 115,18 oxido 1,4- pregnadiene 17a,18,21 triol3,20 di0ne.In a manner similar to that described in Example 5F, treatthe triacetate of Example 8F with methanolic sodium hydroxide at 0 C.Isolate and purify the resultant product in the manner described to give90: fluoro 165 methylll5,l8 oxido 1,4 pregnadiene 17oc,18,21 triol-3,20-dione.

Example 9.6-substituted-I-dehydroaldosterones A. 6 substituted 1701,2021bis methylenedioxy- 1,4 pregnadiene 115 ol 3-0nes.In a manner similar tothat described in Example 4A, treat each of 60a methyl- 1,4 pregnadiene1l5,17a,2l triol 3,20 dione, 6afiuoro 1,4 pregnadiene 115,17u,2l triol3,20-dione, 60:,160: dimethyl 1,4 pregnadiene 11,8,17oc,21 triol- 3,20dione, and 6a fluoro 16a methyl 1,4 pregnadiene ll5,17a,21 tn'ol 3,20dione in chloroform with 37% formaldehyde and hydrochloric acid. Isolatethe respective resultant products in the described manner to give 60:methyl 17 z,20;20,21 bis methylenedioxy- 1,4 pregnadiene 115 o1 3 one,6oc-fiuOI0-l7oz,20; 20,21 bis methylenedioxy 1,4 pregnadiene 115-ol3-one, 6a,].6oc dimethyl 17a,20;20,21 bis methylenedioxy 1,4 pregnadiene115 01- 3 one, and 6ot-fiuoro- 16a methyl 17a,20;20,2l bismethylenedioxy 1,4- pregnadiene-115-ol-3-one, respectively.

B. 6 substituted 17oc,20,'20,21 bis methylenedioxy- 1,4 pregnadiene I15ol 3 one II-nitrite esters.In a manner similar to that described inExample 1A, esterify each of the 115 hydroxy 17a,20;20,21 bismethylenedioxy 1,4 pregnadiene prepared in the preceding example withnitrosyl chloride in pyridine at 20 C. Iso late and purify the resultantrespective products in the described manner to give 6a methyl17u,20;20,21-bis methylenedioxy 1,4 pregnadiene 115 ol 3 one ll-nitrite,6a fluoro l7oz,20;20,2l-bis-methylenedioxy- 1,4 pregnadiene 115 ol 3 one11-nitrite, 6a,16a

dimethyl 17a,20;20,21 bis methylenedioxy 1,4-

pregnadiene 115 ol 3 one ll-nitrite, and 6a-fluoro- 16m methyll7a,20;20,21 bis methylenedioxy 1,4- pregnadiene 115 ol 3 onell-nitrite, respectively.

C. 6 substituted ]7oz,20,'20,21 bis methylenedioxy- 18 oximino 1,4pregnadiene 115 ol 3 ones.-Ir1

' a manner similar to that described in Example 1B, ir-

radiate a toluene solution of each of the ll-nitrite esters prepared inthe preceding example by means of a Hanovia 500 Watt high pressuremercury lamp. Isolate and purify the resultant respective products inthe manner described to give 60: methyl l7a,20;20,21 bis methylenedioxy-18 oximino 1,4 pregnadiene ol 3 one, 6afiuoro l7a,20;20,21 bismethylenedioxy 18-oximino- 1,4 pregnadiene 115 ol 3 one, 60:,1604dimethyl- 17a,20;20,21 bis methylenedioxy 18 oximino 1,4- pregnadiene115 ol 3 one, and 60a fluoro cmethyl 17oc,20;20,21 bis methylenedioxy l8oximino- 1,4-pregnadiene-1 l5-ol-3-one, respectively.

D. 6substituted-115,18-0xid0-18,21-mono-methylenedioxy-1,4-pregnadiene-17a-0l-3,20-di0nes.-Ina manner similar to that described in Example 1C, treat an acetic acidsolution of each of the 18-oximino derivatives prepared in Example 90with 5% aqueous sodium nitrite. Isolate and purify the respectiveresultant products in the described manner to give 6u-methyl-l'l5,l 8oxido-l8,2lmono-methylenedioxy 1,'4 pregnadiene 17a o1-3,20- dione,6u-fluoro-11-5,18-oxido 18,21 monomethylenedioxy-1,4-pregnadiene-17u-ol-3,-20-dione, 6a,16u-dimethy-l-115,1-8-oxido 18,21mono-methylenedioxy-1,4-pregnadiene-17u-ol-'3,20-dione, and6a-fluoro-16a-methyl-115,18- oxido 18,21 mono methylenedioxy1,4-pregnadiene- 17u-ol-3,20-dione.

E. 6 substituted 115,18;18,21 bis-xid0-1,4-pregnadiene-I7u-0l-3,20-di0ne.-In a manner similar to that described in Example 1D,treat an aqueous solution of each of the 18,21-mono-methylenedioxyderivatives prepared in Example 9D with concentrated sulfuric acid at 0C. Isolate and purify the respective resultant products in the mannerdescribed to give6aamethyl-l15,l-8;18,21=bisoxido-1,4-pregnadiene-17aol-3,20-di0ne, 6ozfluoro 1'15, 18;18,2l-bis-oxido-1,4-pregnadiene-17a-o1-3, 20-dione, 6oz,16 xdimethyl-1 l5,l8;18,21-bis oxido 1,4 pregnadiene- 17a-ol-3,20-dioneand 6a-fluoro-16a-metl1yl-115,18;18,21-bis-oxido-l,4-pregnadiene-17a-ol-3,20-dione, respectively.

P. 6-substituted-17ot-hydroxy-1-dehydroaldosterone triacetate esters.1na manner similar to that described in Example 1E, treat an acetic acid/acetic anhydride solution of each of the 115,18;18, 21-bis-oxidoderivatives prepared in Example 9E with 70% aqueous perchloric acid at 5C. Isolate and purify the respective resultant products in the mannerdescribed to give 6a-methyl-115,18-oxid0 1,4- pregnadiene l7oc,18,21triol 3,20 dione triacetate, 60cfluoro 115,18 oxidol,4-pregnadiene-17a,18,2l-triol- 3,20-dione triaceta-te,6a,l6oc-dimethyl-l l5,18oxido-1,4-pregn-adiene-17a,18,2l-triol-3,20dione tria'ceta-te, and 6afluoro 16amethyl 1l5,18-oxido-1,4 pregnadiene-17m, 1-8,21-triol-'3,20-dionetriacetate, respectively.

G. 6-substituted-17a-hydr0xy-1-dehydr0ald0ster0nes.- In a manner similarto that described in Example 1F, hydrolyze each of the1'7a-hydroxyl-dehydroaldosterone triacetate esters prepared in Example9F with aqueous methanolic sodium hydroxide at 0 C. Isolate and purifythe resultant respective products in the manner described to give6u-met-hyl-'115,18-oxido-1,4-pregna'diene-17u,18, 21-triol-3,20-di0ne,6oz fluoro 115,18-oxido-1,4-pregnadiene-17a,18,21-triol-3,20-dione,6u,'16ot-dimethyl-115,18-oxido-1,4-pregnadiene-17a,18,-21-triol-3,20-dione, and 6a.- fiuoro16a-methyl-115,1-8-oxido-1,4-pregnadiene 17a,18, 21-triol-3,20-dione,respectively.

Example 1 0.-1,6-bis-dehydra-1 7a-hydr0xyaldoster0nes A. 17a,20;20,21bis-methylenedioxy-I8-0ximino-1,4, 6-pregnatriene-1l 5-0l-3-0nes.In amanner similar to that described in Example 4A, treat each of1,4,6-pregnatriene- 1 15,17052141101310410116, 9afluoro-1,4,6-pregnatriene- 1l5,17a,21-triol-3,20-dione, and9u-fluoro-16e-methyl-1, 4,6-pregnatriene-1 15,17a,'2-1-triol-3,20-dionewith formaldehyde and concentrated hydrochloric acid in chloroform andisolate the resultant respective products in the manner described togive, respectively, 17a,20;2(),2lbiS-In6thylenedioxy-1,4,6-pregnatriene-115-01-3-one, 9oz fluoro-17a,20;20,2l=bis-methylenedioxy-1,4,6-pregnatriene 115 ol- 3-one, and9a-fluoro-1Got-methyl-17a,20;20,-21-bis-methylenedioxy-l,4,6-pregnatriene-1-15ol-3-one.

In a manner similar to that described in Example 1A, esterify each ofthe 1'15-hydroxy-b'is-methy1enedioxy derivatives prepared above withnitrosyl chloride in pyridine and isolate the resultant respectiveproducts in the manner described to give, respectively,17oz,'20;20,2l-bis-methylenedioxy-1,4,6-pregnatriene-115-ol-3-one 11-nitrite, 9ozfiu01Ol7oc,20;20,-21bi5 methylenedioxy 1,4,6pregnatriene-1l5-ol-3-one ll-nitrite, and 9u-fluoro-16m-methyl-'l7u,20;20,21 bis methylenedioxy 1,4,6- pregnatriene- 115-ol-3-one 1l-n'itrite.

In a manner similar to that described in Example 1B, irradiate a toluenesolution of each of the ll-nitrite esters prepared in the precedingparagraph by means of a Hanovia 500 Watt mercury arc lamp. Isolate theres-pec tive resultant products in the described manner to obtain,respectively, l8-oximino-17a,20;-20,2l-bis-methylenedioxy-1,-4,6-pregnatriene-1 15-ol-3-one, 9a fluoro 18-oximino- 17oc,20;20,2l-bis-methylenedioxy-tl,4,6 pregnat-riene-1l5- ol-3-one, and9a-fluo-ro-1fiu-methyl-l8-oximino-17a,20;20, 2 l-bis-methy-lenedioxy- 1,4,6-pregnatriene-1 15-ol-3one.

B. 115,18 oxido 18,21 mono-methylenedioxy-J,4,6-pregnatriene-l7a-0l-3,20-di0nes.--In a manner similar to that describedin Example 1C, treat each of the 18- oxirnino derivatives prepared inExample 10A with aqueous sodium nitrite in acetic acid and isolate theresult-ant respective products in a manner similar to that described toobtain, respectively, 115,18-oxido-18,21-mono-methylenedioxy-l,4,6-pregnatriene-l7a-ol-3,20-dione, 9a fluoro-115,18-oxido-l 8,2l-mono-methylenedioxy 1,4,6pregnat-riene-17u-ol-3,20dione, and 9a -fiuoro-16a-methyl-115,18-oxido-18,2l-mono-methylenedioxy-1,4,6 pregnatrienc- 173,2017y 11 i C.1 15,1 8;] 8,21 -bis-0xid0-1,4,6 pregnatrz'ene-17a-0l-3, 20-di0nes.(l)In a manner similar to that described in Example 1D, treat115,18-oxido-18,21-mono-methylenedioxy-1,4,6-pregnatriene-l7oz ol 3,20d'ione in aqueous dioxan at 0 C. with concentrated sulfuric acid.Isolate the resultant product in the described manner to give 115,18,18,2l-bis-oxido-l,4,6-pregnatriene-17a-ol-'3,20 dione.

(2) In a manner similar to that described in Example 5D, treat each of9a-fluoro-115,18-oxido-18,21-monomethylenedioxy-l,4,6-pregnatriene-17u-0l-3,20-dioneand 9a fluoro 16a methyl 115,18 oxido 18,21 monomethylenedioxy 1,4,6pregnatriene 17cc o1 3,20 dione in glacial acetic acid and aceticanhydride at 20 C. under nitrogen with 47% aqueous hydriodic acid.Isolate the resultant respective products in a manner similar to thatdescribed to obtain, respectively, 9a-fiuoro-115,l8;18,21-bis-oxido-1,4,6-pregnatriene-l7a-ol-3,20-dione and 9a fluoro -16rxmethyl 115,18;18,21 bis oxido 1,4, 6-pregnatriene-17u-0l-3,20-dione. D.115,18 oxido 1,4,6 pregnatriene 17a,18,21- triol-3,20-di0netriacetates.ln a manner similar to that described in Example 1E, treateach of the 115,18;18,21- bis-oxido derivatives prepared in Example 10Cwith 70% aqueous perchloric acid in acetic acid and acetic anhydride at5 C. Isolate the resultant respective products in the manner describedto obtain, respectively, 115,18-oxido-l,4,6-pregnatriene-17a,18,21-triol-3,20dione triacetate,9oc-fll1OIO-l 15,18-oxido-1,4,6-pregnatriene-17a,l 8,21-triol-3,20-dione triacetate, and 9a-fluoro-16a-methyl-115,18-oxido-1,4,6-pregnatriene-17a,18,21-triol-3,20-dione triacetate.

E. 115,18 oxido 1,4,6 pregnatriene 17a,18,21- tri0l-3,20-diones.-In amanner similar to that described in Example 1F, hydrolyze each of thetriacetate ester derivatives prepared in Example 10D in methanol at 0 C.with aqueous sodium hydroxide. Isolate the resultant respective productsin the manner described to obtain, respectively, 115,18 oxido 1,4,6pregnatriene :,18,

21 triol 3,20 dione, 9a fluoro 115,18 oxido 1,4,6-

pregnatriene-17u,18,21-triol-3,20-dione, and 9u-fiuoro- 16oz methyl115,18 oxido 1,4,6 pregnatriene 170:,

, 18,21-triol-3 ,ZO-dione.

Example 11.[3,2-c]-pyrazoles of 17a-hydroxyald0sterones A. 160; methyl18 oximino 17a,20;20,21 bismethylenedioxy 4 pregnene 115 0l [3,2-c]pyrazoles.In a manner similar to that described in Example bismethylenedioxy 4 pregnene 115 ol [3,2-c] 2'- p fluorophenylpyrazole,16oz methyl 17a,20;20,2l bisrnethylenedioxy 4 pregnene 115 ol [3,2-c] 2'p- 1601 methyl 17a,20;20,21 bismethylenedioxy 4 pregnene 115 ol [3,2-c]2'- phenylpyraz-ole, 16oz methyl l7u,20;20,2l bis methylenedioxy 4pregnene 115 o1 [3,2-c] 1' phenylpyrazole, 6,16oc dimethyl-17zx,20;20,21 bis methylenedioxy 4,6 pregnadiene 115 ol [3,2-c] 2'phenylpyrazole, 6,160: dimethyl 9a fluoro 17a,20;20,21 bismethylenedioxy4,6 pregnadiene 115 ol [3,2-c] 2- phenylpyrazole, and 6,1641 dimethyll7oz,20;20,21 bismethylenedioxy 4,6 pregnadiene 115 01 [3,2-c] 2'-'p-fluor-ophenylpyrazole with nitrosyl chloride in pyridine and isolatethe resultant respective products in a manner similar to that describedto yield, respectively, 9a-fluoro- 16cc methyl 17a,20;20,21 bisInethylenedioxy 4- pregfien'e 1 15 ol [3,2-c] 2' p fluorophenylpyrazole11 nitrite, 16cc methyl 17a,20;20,21 bis methylenedioxy 4 pregnene 115ol [3,2-c] 2 p fluorophenylpyrazole 11 nitrite, 1600 methyl 17a,20;20,21bismethylenedioxy 4 pregnene 115 o1 [3,2-c] 2'- phenylpyrazolell-nitrite, 16a methyl 17a,20;20,21- bis methylenedioxy 4 pregnene 115-ol [3,2-c] 1'- phenylpyrazole 11 nitrite, 6,160: dimethyl 1741,20;20,21 bis methylenedioxy 4,6 pregnadiene 115 ol- [3,2-c]-2phenylpyrazole 11 nitrite, 6,160; dimethyl 9a fluoro 17oz,20;20,21 bismethylenedioxy 4,6- pregnadiene 115 ol [3,2-c] 2' phenylpyrazole 11-nitrite, and 6,16a dimethyl 17u,20;20,21 bis methylenedioxy 4,6pregnadiene 115 ol [3,2-c] 2 pfluorophenylpyrazole 11 nitrite.

In a manner similar to that described in Example 1B, irradiate a toluenesolution of each of the ll-nitrite esters prepared in the precedingparagraph with ultraviolet light from a 500 Watt Hanovia mercury arclamp and isolate the resultant respective products in a manner similarto that described to yield, respectively, 9a-fiuoro-16a-methyl17a,20;20,21 bis methylenedioxy 18 oximino 4- pregnene 115 ol [3,2-c] 2'p fluorophenylpyrazole, 16cc methyl 17a,20;20,21 bis methylenedioxy-18-oxirnino 4 pregnene 115 ol [3,2-c] 2 p fluorophenylpyrazole, 16amethyl 17a,20;20,21 bismethylenedioxy 18 oximino 4 pregnene 115 ol-[3,2-c] 2' phenylpyrazole, 16a methyl 171x,20;20,21 bis methylenedioxy18 oximino 4 pregnene 115- 01 [3,2-c] 1 phenylpyrazole, 6,160: dimethyl17oz, 20;20,21 bis methylenedioxy 18 oximino 4,6 pregnadiene 115 o1[3,2-c] 2' phenylpyrazole, 6,160:- dimethyl 90c fluoro 17u,20;20,21 bismethylenedioxy 18 oximino 4,6 pregnadiene 115 ol [3,2-c]- 2phenylpyrazole, and 6,160: dimethyl 170:,2O;20,21- bis methylenedioxy 18oximino 4,6 pregnadiene- 115 ol [3,2-c] 2' p fluorophenylpyrazole.

B. 115,18 oxido 18,21 mono methylenedioxy 4- pregnene 17oz ol 20 one[3,2-c] pyrazles.In a manner similar to that described in Example 1C,treat each of the 18-oximino derivatives prepared in Example 11A withaqueous sodium nitrite in acetic acid. Isolate the resultant respectiveproducts in a manner similar to that described to obtain, respectively,9a-fluoro-16a-methyl 115,18 oxido 18,21 mono methylenedioxy 4- pregnene17a ol 20 one [3,2-c] 2 p fluorophenylpyrazole, 16a methyl 115,18 oxido18,21- mono methylenedioxy 4 pregnene 17a o1 20 one- [3,2-c] 2 pfluorophenylpyrazole, 16o: methyl 115, 18 oxido 18,21 monomethylenedioxy 4 pregnene- 17oz phenylpyrazole, 16a methyl 115,18 oxido18, 21 mono methylenedioxy 4 pregnene 7a ol 20- one [3,2-c] 1'phenylpyrazole, 6,1611 dimethyl 115, 18 oxido 18,21 mono methylenedioxy4,6 pregnadiene 17a ol 20 one [3,2-c'] 2' phenylpyrazole, 6,160:dimethyl 9a fluoro 115,18 oxido 18,21- mono methylenedioxy 4,6pregnadiene 17m ol 20- one [3,2-c] 2' phenylpyrazole, and 6,16adimethyl- 115,18 oxido 18,21 mono methylenedioxy 4,6 pregnadiene 17oz o120 one [3,2-c] 2' p fluorophenylpyrazole.

C. J15,18;18,21 bis oxido 4 pregnene 17a ol- 20 one [3,2-c]pyraz0les.(1) In a manner similar to that described in Example D, treateach of 9a-fiuoro- 16cc methyl 115,18 oxido 18,21 mono methylenedioxy 4pregnene 17a ol 2O one [3,20-c] 2 pfluorophenylpyrazole and 6,16adimethyl 9a -fluoro- 115,18 oxido 18,21 mono methylenedioxy 4,6pregnadiene 17oz ol 20 one [3,2-c] 2' phenylpyrazole in acetic acid andacetic anhydride with 47% aqueous hydriodic acid. Isolate and purify theresultant respective products in a manner similar to that described toyield 90: fluoro 16oz methyl 115,18;18,21 bis oxido 4- pregnene 17a ol20 one [3,2-c] 2' p fluorophenylpyrazole and 6,160: dimethyl 90c fluoro115,18;l8,

18 21 bis oxido 4,6 pregnadiene 17a ol 20 One- [3,2-c] 2'phenylpyrazole, respectively.

(2) In a manner similar to that described in Example 1D, treat each ofl6a-methyl-115,18-oxido-18,21-monomethylenedioxy-4-pregnene-17ot-ol-20-one[3,2-c] 2-p fluorophenylpyrazole, 6a-methyl 115,18 oxido 18,21-mono-methylenedioxy-4-pregnene-17a-ol-20-one [3,2-c]- 2-phenylpyrazole,16a-methyl-1 15,1 8-oXido-18,21-monomethylenedioxy-4-pregnene-l7a-ol 2Oone [3,2-c]-lphenylpyrazole, 6, 16a-dimethy1 1 15,18 oxido 18,21-mono-methylenedioxy-4,6-pregnadiene-1711-01-20 one-[3,2-c]-2-phenylpyrazole, and 6,16a-dimethyl-115,l8-oxido-18,21-mono-methylenedioxy4,6-pregnadiene-17a o1 20-one-[3,2-c]-2-p-fluorophenylpyrazole in aqueous dioxan with concentratedsulfuric acid. Isolate the resultant respective products in a mannersimilar to that described to yield 16a-methyl-1l5,18;18,21-bis-oxido 4pregnenel7ot-ol-20-one-[3,2-c] 2' p-fiuorophenylpyrazole,16ozmethyl--18;18,21-bis-oxido-4-pregnene-17a-ol-20 one-[3,2-c]-2phenylpyrazole, 16a-rnethyl-115,18;18,21 bis-0xido-4-pregnene-17u-ol-20-one-[3,2-e] 1 phenylpyrazole,6,16a-dimethyl-115,18;18,21-bis-oxid0 4,6pregnadiene-l7u-ol-20-one-[3,2-c]-2-phenylpyrazole, and 6,1611-dimethyl-l 15,1 8 ;18,21-bis-oxido-4,6 pregnadiene-17u-ol-20-one-[3,2-c]-2-p-fluorophenylpyrazole.

D. loa-methyl-l 7a-hydroxyaldosterones [3,2-c]-pyraz0les.In a mannersimilar to that described in Example 1E, treat each of thel115,18;18,21-bis-oxido derivatives prepared in Example 11C with aqueousperchloric acid in acetic acid and acetic anhydride. Isolate theresultant respective products in a manner similar to that described toyield, respectively, 9a-fiuoro-16a-methyl-115,18-oxido-4-pregnene-17a,18,21-triol-20-one [3,2-c] 2'-p fluorophenylpyrazoletriacetate, 16a-methyl-115,18 oxido 4-pregnene-17u,18,21-triol-20-one-[3,2-c]-2-p fluorophenylpyrazoletriacetate, 16a-rnethyl-115,18-oxido-4-pregnene-17u, 18,21-triol-20-one-[3,2-c]-2-phenylpyrazole triacetate,16a-methyl-115,18-oxido-4-pregnene 17 11,18,21-triol-20-one-[3,2-c]-lphenylpyrazole triacetate,6,16a-dimethyl-115,18oxido-4,6-pregnadiene 17a,18,2l-triol-20-one-[3,2-c]-2'-phenylpyrazole triacetate, 6,16a-dimethyl-9a-fiuoro-115,18-oxido 4,6 pregnadiene-17u,18,2l-triol-20-one-[3,2-c]-2'-pheny-lpyrazole triacetate, and6,16a-dimethyl-115,18-oxido-4,6-pregnadiene-17u,18,21 triol-20-one-[3,2-c]-2'-p-fluorophenylpyrazole triacetate.

Hydrolyze each of the triacetate ester derivatives prepared in thepreceding paragraph in methanol at 0 C. With aqueous sodium hydroxide ina manner similar to that described in Example 1F, and isolate theresultant respective products in a manner similar to that described toyield, respectively, 9a-fluoro-16a-methyl-115,18-oxido- 4-pregnene17a,18,21-triol-20-one [3,2-c] 2'-p-fiuorophenylpyrazole, 16a-methyl-115,18-oxido-4-pregnene-17ar 18,21-triol-20-one-[3,2-c]-2'-pfluorophenylpyrazole, 16amethyl-l15-18-oxid0-4-pregnene-17a,18,21-triol20 one- [3,2-c]-2-phenylpyrazole, 16a-methy1 115,18 oxide-4.-pregnene-17a,18,21-triol-20-one [3,2'c] 1-phenylpyra zole,6,16u-dimethyl-1l5,18-oxido-4,6 pregnadiene 17oz,18,21-triol-20-one-[3,2-c] 2 -phenylpyrazole, 6,16a-dimethyl-9a-fluoro-115,18-oxido-4,6-pregnadiene-17m,18,2ltriol-20-one-[3,2-c]-2-phenylpyrazole,and 6,16a-dimethyl-115,18-oxido-4,6-pregnadiene-17a,18,2lrtriol 20 one-[3,2-c]-2-p-fiuorophenylpyrazole.

Example 12.6-dehydr0-17u-hydr0xyald0ster0nes By going through a seriesof reactions similar to those described in Example 10, i.e., procedures10A through 10E, 6-dehydro-hydrocortisone and6,16a-dimethyl-6-dehydro-hydrocortisone are reacted With formaldehydeand hydrochloric acid in chloroform to yield l7oc,20;20-21-bi$-methylenedioxy-4,6-pregnadiene-1l5-ol-3-one and 6,160;-dimethyl-17a,20;20,21-bis-methylenedioxy-4,6 pregnadiene-l 15-ol-3-one,respectively, which are then esterified with nitrosyl chloride inpyridine to give the corresponding ll-nitrite esters, i.e.,17u,20;20,2l-bis-methylenedioxy- 19 '4,6-pregnadiene-1 1,6-01-3-onell-nitrite yl-17a,20;20,21-bis-Inethylenedioxy-4,6-pregnadienellfiol-3-one ll-nitrite. Irradiation of each of the aforementionednitrite esters in toluene yields 17oz,20;20,2l-bi8- methylenedioxy- 18-oximino-4,6 -pregnadiene-1 1 5-01-3 -one and6,1Gwdimethyl-17a,20;20,2l-bis-methylenedioxy l8-oximiu-4,6-pregnadiene-l lB-ol-3-one, respectively, each of which, upontreatment with nitrous acid, are converted to 1 18,18-oxido-18,21-mono-methylene-dioxy-4,6-pregnadiene-17a-ol-3,20-dioneand 6,].60c-(llt1'16tl1Yl-11B,18-0X.ldOl8,2lmono-methylenedioxy-17a-ol-3,20-dione, respectively. Treatment ofeach of the l1B,l8-0Xid0-18,21-m0110- methylenedioxy derivatives withconcentrated sulfuric acid in aqueous dioxan at 0 C. yields11;8,18;18,21-bisoxido-4,6-pregnadiene 17a ol 3,20-dione and6,16a-dimethyl-115,18;18,21-bis-oxido-4,6-pregnadiene 17u-ol-3,20-dione, respectively. Treatment of each of the hisoxido derivativeswith 70% aqueous perchloric acid in acetic acid/ acetic anhydride at C.yields 11fl,18-oxido- 4,6-pregnadiene-l7a,18,2l-triol-3,20-dionetriacetate and 6,l6a-dimethyl-l1,8-18-oxido-4,6-pregnadiene 17oc,18,21-triol-3,20-dione triacetate, respectively, which are hydrolyzed inmethanol with aqueous sodium hydroxide to yield '11B,18-oxido-4,6-pregnadiene-l711,18,2l-triol-3 ,20 dione and6,16u-dimethyl-l 1 3,18-oxido-4,6-pregnadiene-l7u,l8, 2l-triol-3,20-dione, respectively.

Example 13.Alternate procedures for the preparation of 1 7a-hydroxyaldosterones A. Treat hydrocortisone 21-acetate with nitrosylchloride in pyridine in a manner similar to that described in Example 1Ato give hydrocortisone ll-nitrile 21-acetate.

In a manner similar to that described in Example 1B, dissolvehydrocortisone ll-nitrite 21-acetate in toluene and irradiate thetoluene solution with ultraviolet light and isolate the resultantproduct in a manner similar to that described to givel8-oximino-hydrocortisone 21-acetate.

React 18-oximino-hydrocortisone 21-acetate with 5% aqueous sodiumnitrite in acetic acid in the manner described in Example 1C. Purify theresultant product by extracting the reaction mixture several times withmethylene chloride, wash the combined extracts with aqueous sodiumbicarbonate, dry over sodium sulfate, and evaporate in vacuo to aresidue of substantially l7ot-hydroxyaldostcrone. Purify bycrystallization from ethyl acetatemethanol.

B. The requisite intermediate, 3,20-bis-ethylenedioxy-5-pregnene-11fi,17a,21-triol 11-nitrite 2l-acetate, is prepared from3,20-bis-ethylenedioxy-5-pregnene 1118,1711- 2l-triol ZI-acetate byreaction with nitrosyl chloride in pyridine in a manner similar to thatdescribed in Example 1A.

Irradiate a solution of 10 g. of 3,20-bis-ethylendioxy- S-pregnene-ll/3,17a,21-triol ll-nitrite 2l-acetate in 130 ml. of benzene at 10C.under nitrogen for 90 minutes in a manner similar to that described inExample 1B. Evaporate the benzene in vacuo and triturate the resultantresidue with acetone to give3,20-bis-ethylenedioxyl8-oximino-5-pregnene-1 l;3,17a,21-trio121-acetate. Purify by recrystallization from acetone.

To 200 mg. of 3,20-bis-ethylenedioxy-l8-oximino-5-pregnene-11fl,17a,21-triol 21-acetate in 13 ml. of glacial acetic acid,add 6.5 ml. of 5% aqueous sodium nitrite at room temperature. Allow thesolution to stand at room temperature for 15 minutes; then pour intowater and extract with methylene chloride. Wash the combined methylenechloride extracts with aqueous sodium bicar- Ibonate, dry over sodiumsulfate, and evaporate in vacuo to a residue of substantially3,20-bis-ethylenedioxy-11,8, 18-oxido-5-pregnene-17a,18,2l-triol21-acetate. Purify by crystallization from ethyl acetate-hexane.

To 300mg. of 3,20-bis-ethylenedioxy-115,18-oxido-5-pregnene-17a,18,21-triol 21-acetate in 18 ml. of dioxan containing42 ml.of water add 3.6 ml. of concentrated and measles.

r .20 r sulfuric acid and heat the reaction mixture under nitrogen on asteam bath for 1% hours. Add water to thereaction mixture, extract withmethylene chloride, then distill the combined methylene chloridefractions to a residue of substantially11fi,18;18,2l-bis-oxido-4-pregnene-17o:- ol-3,20-dione (the compound ofExample 4E). Purify by crystallization from ethyl acetate.

Reaction of the bis-oxido derivative prepared in the preceding paragraphin the manner described in Examples 4F and 4G will yield17a-hydroxyaldosterone.

Example 14 '3,20-dione diacetate which is dehydrobrominated in refiuxingpyridine to yield 9a-fluoro-l6-methyl4 15,18- oxido-1,4,16-preguatriene-18,21-diol-3 ,ZO-dione diacetate.

The 16-bromoand 16-dehydroaldoste1'one derivatives such as thosedescribed below have minimal sodium retaining properties, are valuableas anti-aldosterone agents, and are valuable as intermediates inpreparing other therapeutically valuable derivatives.

A. 9ozuoro-l6a-bromo-l1fi,18-0xid0-16,8-methyl-L4- pregnadiene18,2]-di0l-3,20-di0ne diacetate.To 2.4 g. of9a-fluoro-.16u-methy1-(11fl,18-oxido-18,21-mono-methylenedioxy-l,4-pregnadiene-l7a-ol-3,20-dione(the compound of Example 5C) dissolved in 74 ml. of glacial acetic acidat room temperature, and dropwise a solution of 28 g. of gaseoushydrogen bromide in 94 g. of glacial acetic acid over a period of 1%hours. Evaporate the reaction mixture to a residue; then dissolve theresidue in methylene chloride and chromatograph over Florisil. Combinethe like fractions and evaporate to a residue comprisingz-flI10I'O-16oc-bIOm0-115,18-oxido-16B-methyl-l,4-pregnadiene-l8,21-diol-3,20-dione diacetate.

In a similar manner,115,18-oxido-18-2l-mono-methylenedioxy-1,4pregnadiene-17a-ol-3,20-dione,9a-fiuoro- 116,18 oxido 18,21.-mono-methylenedioxy-4-pregnene- 17ozol-3,20-dione,9a-fluoro-11/3,l8-oxido-18,21-monomethylenedioxy-l,4-pregnadiene-1711-01-3,ZO-dione, 11B, 18 oxido 18,21-mono-methylenedioxy-4-pregnene-17aol-3,20-dione, 9a-bromo-11,B,18-oxido-18,21-mono-methylenedioxy-4-pregnene-l7a-ol-3,20-dione, and16u methyl11,8,l8-oxido-18,2l-mono-methylenedioxy-1,4,6-pregnatriene-l7a-ol-3,20-dione(the compounds of Examples 1C, 2C, 3A, 4D, 7C, and 10B, respectively)upon reaction with hydrogen bromide in acetic acid in the abovedescribedmanner are each converted to 'IGm-bI'OIHO-llfl, l8oxido-1,4-pregnadiene-18,2l-diol-3,20-dione diacetate,9a-fiuoro-16a-bromo-1 1,8,18-oxido-4-pregnene-18,21- diol-3 ,20-dionediacetate, 9oc-flL101'O-I6cc-bXOII10-l15,18-

0xido 1,4-pregnadiene-18,21-diol-3,20-dione diacetate,

a bromo 115,18-oxido-4-pregnene-18,2l-diol-3,20- dione diacetate,9a,l6a-dibromo-l1,3,18-oxido-4-pregnene-l8,21-diol-3,20dione diacetate,and 16a-bromo-16B- methyl11,8,l8-oxido-l,4,6-pregnatriene-18,21-diol-3,20- dione diacetate,respectively.

B. 9u-flu0r0-1 1 13,18-oxid0-16-methyl-I,4,16-pregnatriems-18,21-di0l-3,20-di0nediacetate.Add 82 mg. of 90cfluorol6a-bromo-11B,18-oxido-16B-methyl-l,4-pregnadime-18,21-diol-3,20-dionediacetate to 2.5 ml. of pyridine and reflux the solution for 40 minutes.Chromatograph the resultant product over 2 g. of alumina in methylenedichloride containing 1% methanol. Evaporate the eluate in vacuo to aresidue comprising 9a-fiuoro-ll 3,18- oxido16-methyl-1,4,16-pregnatriene-18,21-diol-3,20-dione diacetate. Purify bycrystallization from acetonehexane.

In a similar manner, treat each of the 16u-bromo derivatives prepared inExample 14A in refluxing pyridine and isolate the resultant products inthe described manner to give, respectively,11e,18-oxido-1,4,16-pregnatriene-18,21- diol3,20-dione diacetate,9oc-fiI1OIO-11,8,18-0Xid0-4,l6- pregnadiene-18,21-diol-3,20 dionediacetate, 9a-fluoro-11,3,18-oxido-1,4,l6-pregnatriene-18,2-diol-3,20-dione diacetate,1113,18 oxido-4,16-pregnadiene-18,21-diol-3,20- dione diacetate,9u-bromo-115,18-oxido-4,'16-pregnadiene-l8,21-diol-3,20-dione diacetate,and 115,18-oxido-16- methyl-1,4,6,l6pregnatetraene-18,2l-diol-3,20-dione diacetate.

I claim:

1. A member selected from the group consisting of a [3,2-c]-pyrazolederivative of a l7a-'hydroxyaldosterone of the following formula and the6-dehydro analogs thereof:

l -CH CHaOR wherein A is a member selected from the group consisting ofhydrogen and lower alkyl; B is a member selected from the groupconsisting of hydrogen, methyl, and fluorine; X is a member selectedfrom the group consisting of hydrogen and halogen; and R, R, and R" aremembers selected from the group consisting of hydrogen and loweralkan-oyl; wherein said [3,2-c]-pyrazole derivative is a member selectedfrom the group consisting of [3,2-c] -2'-p-:Eluorophenylpyrazole,[3,2-c]-2'- phenylpyrazole and [3,2-c]-1-phenylpyrazole.

2. 9a fluoro 115,18 oxido 16a methyl 4 pregnene 17a,18,21 triol 3,20dione [3,2-c] 2 p fluorophenylpyrazole.

3. 9oz fluoro 11B,18 oxido 16oz methyl 1,4-pregnadiene-l7a,l8,21-triol-3,20-dione.

4. 9a fluoro 1 15,18 oxido 16a methyl 1,4-pregnadiene-l7u,l8,2l-triol-3,2 0-dione triacetate.

5. A compound selected from the group consisting of18,2l-mono-methylenedioxy-4-pregnenes of the following formula, thel-dehydro, G-dehydr-o, and 1,6-bis-dehydro analogs, the[-3,2-c]-pyrazole derivatives thereof of the group consisting of[3,2-c]-2'-p-fluorophenylpyrazole, [3,2-c]-2-phenylpyrazole, and[3,2-c]-1-phenylpyrazole, and the 6-dehydro analogs of said[3,2-c]-pyrazole de rivatives thereof:

wherein A is a member selected from the group con sisting of hydrogenand lower alkyl; B is a member selected from the group consisting ofhydrogen, methyl,

and fluorine; and X is a member selected from the group consisting ofhydrogen and halogen.

6. A compound selected from the group consisting of an18,2l-oxido-4-pregnene of the following structural formula, the.l-dehydro, 6-dehydro, and 1,6-bis-dehydroanalogs, the [3,2-c]-pyrazolederivatives thereof of the group consisting of[3,2-c]2-p-fluorophenylpyrazole,. [3,2c]-2'-phenylpyrazole; and[3,2-c]-l'-phenylpyrazole, and the 6-dehydro analogs of said[3,2-c]-pyrazole derivatives thereof:

wherein A is a member selected from the group consisting of hydrogen andlower alkyl; B is a member selected from the group consisting ofhydrogen, methyl, and fluorine; and X is a member selected from thegroup consisting of hydrogen andv halogen.

7. A compound selected from the group consisting of 18-oximinoderivatives of the following structural formula, the l-dehydro,6-de'hydro, and 1,6-bis-dehydro analogs, and the [3,2-c]-pyrazolederivatives thereof of the group consisting of[3,2-c]-2'-p-fluorophenylpyrazole, [3,2-c] -2'-.phenylpyrazole, and[3,2-c]-1'-phenylpyrazole, and the 6-dehydro analogs of said[3,2-c]-pyrazole derivatives thereof:

O-GH; on;

N 0-0-0 CI iE CH, LHO/ 011$ QM A 0.0

wherein A is a member selected from the group consisting of hydrogen andlower alkyl; B is a member selected from the group consisting ofhydrogen, methyl, and fluorine; and X is a member selected from thegroup consisting of hydrogen and halogen.

8. In the process of preparing a 17a-hydroxyaldosterone the step whichcomprises treating with nitrous acid a member of the group consisting ofthe 2l-lower alkanoate, the 3,20bis-lower alkylene ketal derivatives,and the 17or.,20; 20,2l-bis-methylenedioxy derivative of an18-oximino-4- pregnene-l1,8,17u,21-triol-3,20-dione.

9. In the process of preparing 17a-hydroxyaldosterone the steps whichcomprise treating with nitrous acid a member of the group consisting ofan 18-oxi1nino-l7a,20;20,21- bis-methylenedioxy-4-pregnene-11r3-ol-3-one and a [3,2-c]- pyrazole derivative thereof, and subjectingthe thereby formed intermediate of the group consisting of an 115,18-oxido-18,21 mono methylenedioxy 4 pIegnene-17a-0l- 3,20-dione and a[3,2-c]-pyrazole derivative thereof to acidic hydrolysis.

10. In the process for preparing a 17u-hydroxyaldosterone, the stepswhich comprise treating with nitrous acid a member of the groupconsisting of an 18-oximino- 17a,20;20,21-bis methylenedioxy 4pregnene-llfi-ol-3- one and a [3,2-c]-pyrazole derivative thereof;subjecting the thereby formed intermediate of the group consisting 231 vl V a of an1113,18-oxido-18,21-mono-methylenedioxy-4-pregnene-l7a-ol-3,20-dione anda [3,2-c1-pyrazole derivative thereof to an acidic reagent of the groupconsisting of sulfuric acid in aqueous dioxan and, when said 4-pregnenehas a 9u-halogeno group, an acetic acid/acetic anhydride in 47%hydriodic acid mixture; reacting a the thereby formed bis-oxidointermediate of the group consisting of 115,18;18,21-bis-oxido-4-pregnene-1711-01-3 ,20-dione and a[3,2-c]-pyrazole derivative thereof to a perchloric acid/ alkanoicacid/alkanoic acid anhydride mixture, whereby there is formed atri-alkanoate of the group consisting of a-17a-hydroxyaldosterone-17a,18,21-tri-alkanoate ester and a [3,2-c]-pyrazole derivative thereof.

11. The process of claim 10 including the subsequent step of subjectingsaid tri-alkanoate of the group consisting of a17a-hydroxyaldosterone-170:,18,21-tri-alkanoate and a [3,2-c1-pyrazolederivative thereof to mild alkaline hydrolysis.

12. In the process for preparing a compound selected from the groupconsisting of 17a-hydroxyaldosterones of the following structuralformula and the l-dehydro, 6-dehydro, and 1,6-bis-dehydro analogsthereof, and the [3,2-c]-pyrazole derivatives thereof, and the 6-dehydroanalogs of said [3,2-c] -pyrazo1e derivatives thereof:

GHzOR ---0R GHJQQ l wherein A is a member selected from the groupconsisting of hydrogen and lower alkyl; B is a member selected from thegroup consisting of hydrogen, methyl, and fluorine; X is a memberselected from the group consisting of hydrogen and halogen; and R, R andR" are members selected from the group consisting of hydrogen and loweralkanoyl; which comprises reacting with nitrous acid a compound selectedfrom the group consisting of an 115- hydroxy-l8-oximino-4-pregnene ofthe following formula and the l-dehydro, G-dehydro, and 1,6-bis-dehydroanalogs thereof, and the [3,2-c1-pyrazo1e derivatives thereof, and theG-dehydro analogs of said [3,2-c]-pyrazole derivatives thereof:

wherein A, B, and X are as above defined; subjecting the thereby formedcompound selected from the group consisting of an 115,18-oxido-l8,21-mono-methylenedioxy-4- pregnene of the followingformula, the l-dehydro, 6-der 24' hydro, and 1,6-bis-dehydro analogsthereof, and the [3,2-c]-pyrazole derivatives thereof, and the 6-dehydro analogs of said [3,2-c] -pyrazole derivatives thereof:

A, B, and X being as above defined, to a perchloric acid/ alkanoicacid/alkanoic acid anhydride mixture, whereby is formed a compoundselected from the group consisting of a 17u,18,21-tri-a1kanoate of thefollowing formula, and the l-dehydro, G-dehydro, and 1,6-bis-dehydroanalogs, and the [3,2-c]-pyrazole derivatives thereof, and the 6-dehydro analogs of said [3,2-c] -pyrazole derivatives thereof:

wherein A, B, and X are as above defined and R is lower alkanoyl.

25 13. The process for preparing a 9a-halogeno-17a-hydroxyaldosteroneselected from the group consisting of compounds of the followingstructural formula and the l-dehydro, G-dehydro, and 1,6-bis-dehydroanalogs, and the [3,2-c]-pyrazole derivatives thereof, and the 6-dehydroanalogs of said [3,2-c] -pyrazole derivatives thereof:

onion 0H? 3W A Egg wherein A, B, and X are as above defined; andtreating with sulfuric acid in aqueous dioxan at temperatures in therange of from 20100 C. the thereby formed 115,18-oxido-l8,21-mono-methylenedioxy derivative selected from the groupconsisting of compounds of the following structural formula and thel-dehydro, 6-dehydro, and 1,6-bisdehydro analogs thereof, and the[3,2-c] -pyrazole derivatives thereof, and the 6-dehydro analogs of said[3,2-c]- pyrazole derivatives thereof:

O (EH3 wherein A, B, and X are as above defined.

14. The process of preparing9a-flu0ro-16u-methyl-17ahydroxy-l-dehydroaldosterone which comprisesreacting 9a-fluoro-18-oXimino-17u,20;20,21 bis methylenedioxy-1,4-pregnadiene-l1fi-ol-3-one with nitrous acid, and subjecting the9a.-fluoro-11fi,18-oXido-18,2l-mono-methylenedioxy-l,4-pregnadiene-17zx-ol-3,20-dionethereby formed to the action of sulfuric acid in aqueous dioxan attemperatures in the range of 80 C.

References Cited by the Examiner UNITED STATES PATENTS 2,882,282 4/59Agnello et a1 260-397.3 2,948,738 8/ 60 Reichstein et al 260240.92,949,405 8/60 Wettstein et al 5 1 3,000,884 9/61 Wettstein et a1260239.57

LEWIS GOTTS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,216,997 November 9, 1965 Derek H, R. Barton ror appears in the abovenumbered pat- It is hereby certified that er he said Letters Patentshould read as ent requiring correction and that t corrected below.

Column 2, line 70, below the formula, for "(Ib) and (lbl)" read (lb) and(Ilb) column 7, line 60, for "of 0.1 aqueous" read of 0.1 N aqueouscolumn 10, line 4, for "llu,l8;l8,2l-bis-oxido-" readllB,l8;l8,2l-bisoxidocolumn 16, line 9, for "173,20l7y 11 readl7c1-Ol-3,ZO-

for "4-pregnene7a-ol-" read D dione column 17, line 52, 4-pregnenel7aolcolumn 18, line 6, for "6a-methylllB,l8- read l6q-,methylll6,l8- column21, line 9, for

1" read pregnatriene-l8,2ldio1 "pregnatriene-l8,2-dio column 23, lines25 to 40, the formula should appear as shown below instead of as in thepatent:

Signed and sealed this 29th day of November 1966.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A (3,2-C)-PYRAZOLEDERIVATIVE OF A 17A-HYDROXYALDOSTERONE OF THE FOLLOWING FORMULA AND THE6-DEHYDRO ANALOGS THEREOF: